Monoacetals of hydroquinone

ABSTRACT

The present invention is for a process for preparing monoacetals of hydroquinone wherein said process provides for higher yields of greater purity. Said process utilizes a two step reaction wherein a protected hydroquinone is reacted with an enol ether to form a protected intermediate. Upon hydrogenolysis of said intermediate a final product, monoacetal hydroquinone, is formed having higher degree of purity and in greater yields that the yields attributed to reactions known in the art.

This is a division of application Ser. No. 08/357,849, filed on Dec. 16,1994, now U.S. Pat. No. 5,585,525.

FIELD OF THE INVENTION

The present invention is for a process for preparing monoacetals ofhydroquinone wherein said process yields higher yields of greater puritythan reactions previously used.

BACKGROUND OF THE INVENTION

The process for making monoacetals of hydroquinone is disclosed inco-pending patent application U. S. Ser. No. 08/206,573, filed Mar. 4,1994 now abandoned; incorporated herein by reference. Said processinvolves reacting equimolar amounts of hydroquinone with enol ethers inthe presence of an acid catalyst: ##STR1## (i) each R is, independently,selected from the group consisting of hydrogen; C₁ -C₁₀ alkyl; benzyl,aryl and substituted benzyl or aryl.

(ii) each R' is, independently, selected from the group consisting of C₁-C₁₀ alkyl; benzyl, aryl and substituted benzyl or aryl.

(iii) n is an integer from 0 to 3.

However, said reaction has several limitations. For equimolarconcentrations of hydroquinone and enol ethers said reaction alsoresults in formation of hydroquinone bis-acetals which are poor skinlightening compounds. Removal of the non-efficacious bis-acetalcompounds, along with unreacted hydroquinone, necessitates expensivelarge scale chromatographic purification such that isolated yield ofsaid monoacetal is poor, typically 30-40%. Attempts at improving overallyield and cost of process via conversion/recycling of bis-acetal todesired monoacetal is problematic due to similar reactivity of the twocompounds, while changing the stoichiometry of the reaction to minimizebis-acetal formation increases the amount of hydroquinone whichultimately needs to be chromatographically removed.

SUMMARY OF THE INVENTION

The present invention is a process for preparing monoacetals ofhydroquinone comprising the steps of:

a) reacting monoethers of hydroquinone with an enol ether in thepresence of an acid catalyst to yield the protected monoacetal ofhydroquinone as an intermediate; and

b) reacting said intermediate with a hydrogen transfer source in thepresence of a metal catalyst such that protecting group is selectivelycleaved to give desired hydroquinone monoacetal.

These reactions produce purer hydroquinone monoacetals in high yieldwithout the need for chromatographic purification.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a novel process for making hydroquinonemonoacetals comprising a series of steps wherein monoethers ofhydroquinone are used to improve the purity and the yield of the desiredfinal product compared to the process previously disclosed. Reaction ofsaid hydroquinone monoether with an enol ether yields an intermediateproduct that is protected from acid catalyzed coupling with a secondequivalent of enol ether, irrespective of the stoichiometry of themonoether compound and enol ether. Utilization of protecting groups toeliminate production of undesirable by-products of synthesis reactionsis well known in the art. In the present invention it is desirable toeliminate or at the very least minimize producing bis-acetalhydroquinone compounds, which if present at the time of the secondprocess step of the present invention, yields undesirable finalproducts. In the subsequent hydrogenolysis of said intermediate product,selective cleavage of ether protecting group provides the final desiredproduct in higher yields with greater purity.

The hydroquinone protecting groups useful in the present invention areethers susceptible to selective hydrogenolysis under mild conditions.Said ethers used as protective groups in the present invention areselected from the group consisting of arylmethyl, diarylmethyl,triarylmethyl, trimethylsilyl ethers and mixtures thereof, preferablyarylmethyl ethers. The preferred arylmethyl ether protecting groups ofthe present invention are selected from the group consisting of benzyl,aliphatic benzyl ethers and mixtures thereof, preferably aliphaticbenzyl ether, most preferably the monobenzyl ether. The monobenzyl etherof hydroquinone may be purchased as monobenzone or 4-(benzyloxy) phenoldirectly from commercial sources such as Aldrich Chemical Company andHoechst Celanese Corporation. Monobenzone may also be produced byroutine chemical reactions well known in the art; see Schiff andPellizzari, Justus Liebig's Annalen Der Chimie, vol. 221, pp370 (1883);incorporated herein by reference.

The said hydroquinone monoether is reacted with cyclic or acyclic enolethers to yield the protected intermediate, preferably the benzylprotected monoacetal of hydroquinone, as illustrated below: ##STR2##wherein: (i) each R is, independently, selected from the groupconsisting of hydrogen; C₁ -C₁₀ alkyl; benzyl, aryl and substitutedbenzyl or aryl.

(ii) each R' is, independently, selected from the group consisting of C₁-C₁₀ alkyl; benzyl, aryl and substituted benzyl or aryl.

(iii) n is an integer from 0 to 3; and po1 (iv) Bn is a benzyl group.

This intermediate product is then subjected to a subsequenthydrogenolysis reaction in order to cleave said benzyl protective groupfrom the intermediate product above to provide the final desiredproduct. Selective removal of hydroxyl protecting above to provide thefinal desired product. Selective removal of hydroxyl protecting groupsincluding O-benzyl groups is known. Bieg and Szeja, Removal of O-BenzylProtective Groups by Catalytic Transfer Hydrogenation, Synthesis,January 1985, discloses the cleavage of benzyl ethers of monosaccharidesusing ammonium formate as a hydrogen donor and 10% palladium on carboncatalyst. It is further disclosed therein that said method may be usedfor the selective removal of O-benzyl ethers in the presence of othertypes of O-protecting groups. Bieg and Szeja,Cleavage of2-Phenyl-1,3-dioxolanes and Benzyl Ethers by Catalytic TransferHydrogenation, Synthesis, April 1986, discloses cleavage of2-phenyl-1,3-dioxolane protective groups by catalytic transferhydrogenation which circumvents the disadvantage of simultaneouscleavage of a 2-phenyl-1,3-dioxane group also present in the molecule.Hydrazine hydrate is used as the hydrogen source and 10% palladium oncarbon as the catalyst. Said reaction may be utilized for preparation ofa whole range of partially protected sugars.

In the present invention the hydrogenolysis step is as illustratedbelow: ##STR3##

Cleavage of the benzyl group is accomplished in virtually quantitativeyield with non-acidic hydrogen transfer sources such as hydrazinehydrate and ammonium formate in combination with a supported metalcatalyst. The acetal portion of the intermediate molecule is unaffectedby these conditions, eliminating the simultaneous formation ofhydroquinone and/or regeneration of monobenzone. Hence there is no needfor any chromatographic separation and the desired compounds can beisolated via simple purification techniques. Overall yield for the twostep process is significantly higher than the previously disclosed onestep process.

Reaction Method

A. STEP ONE

As disclosed above the first step of the process is to produce theprotected intermediate. In the case of the benzyl protecting group,4-(benzyloxy)phenol is combined with a cyclic or acyclic enol ether anda catalytic amount of acid under an inert atmosphere. In general, thestoichiometric ratio of enol ether and 4-(benzyloxy)phenol is from 1:1to 2:1. A variety of acidic sources can be used, preferably thoseselected from the group consisting of hydrochloric acid, sulfuric acid,para-toluenesulfonic acid and mixtures thereof, wherein the catalyticdose does not exceed 0.02 equivalents based on the weight of4-(benzyloxy)phenol. A typical dose is 0.005-0.015 equivalents of acid.Most preferred acidic source is hydrochloric acid.

Formation of the intermediate is conveniently carried out in a varietyof polar organic solvents. Preferred polar solvents include thoseselected from the group consisting of methylene chloride, diethylether,tetrahydrofuran, dioxane and mixtures thereof, most preferred beingmethylene chloride. Typical total reactant concentrations are in the5-15% weight range, although complete solvation of 4-(benzyloxy)phenolis not crucial.

Depending on the amount of starting materials, the intermediate formingreaction takes from about 1 to about 16 hours at room temperature andatmospheric pressure. Changing the order of addition of startingmaterials has no affect on intermediate formation. In general, thereaction can be accelerated and forced to completion via the addition offurther quantities of enol ether. After solvent removal a series ofwashes and triturations with non-polar solvents, typically hexanes,allows purification of the intermediate in high yield, normally greaterthan about 80%. In the present invention a particular advantage of theuse of 4-(benzyloxy)phenol is that large scale chromatographicpurification is not required since any unreacted 4-(benzyloxy)phenol canbe conveniently removed with an aqueous sodium hydroxide wash.

B. STEP TWO

Following the formation of said intermediate in step one, step two ofthe present process involves selective hydrogenolysis of the O-benzylprotecting group. Said hydrogenolysis is accomplished by using anynumber of hydrogen donors. In the present invention it is preferred thatthe hydrogen transfer source is non-acidic and is selected from thegroup consisting of hydrazine, ammonium formate, trialkylammoniumformates, and mixtures thereof; all readily available from commercialsources or which can be made prepared prior to reaction. Hydrazine istypically supplied in the hydrate form (55% w/w hydrazine) which can beused without further purification. The molar ratio of hydrogen transfersource to intermediate is from about 6:1 to about 1:1, preferably 4:1 toabout 2:1, and most preferably 3:1.

Said hydrogenolysis also requires a supported metal catalyst, preferablya carbon supported metal selected from the group consisting ofpalladium, platinum, nickel and mixtures thereof Most preferred ispalladium on carbon. The weight percentage of metal in the supportedcatalyst is from about 2-20%, preferably 5-10%.

The reaction is carried out in an organic solvent which fully dissolvesthe intermediate upon refluxing. The preferred organic solvent is ahydroxy solvent, most preferred are those selected from the groupconsisting of methanol, ethanol, isopropanol and mixtures thereof,preferably methanol and ethanol. Intermediate concentrations aretypically in the 5-15% weight range relative to solvent.

Depending on the amount of starting materials, complete removal ofbenzyl group generally takes from about 0.5 to about 2.0 hours at refluxunder an inert atmosphere. In the present invention a particularadvantage of the use of non-acidic hydrogen transfer sources is thatlarge scale chromatographic purification is not required sinceessentially no hydroquinone or monobenzone byproducts are formed. Theproduct is dried by solvent/water stripping and trituration withnon-polar solvents or recrystallization from water/alcohol mixtures.

With regard to this second step involving reaction of the intermediatewith said hydrogen donor, it is preferred that said intermediate issubstantially free from impurities since they can negatively affect thereaction by, for example, modifying the surface of the preferred metalcatalysts used herein.

EXAMPLE I

4- (Tetrahydrofuran-2-yl)oxy!phenol is prepared as follows: ##STR4##

STEP ONE:

Combine 4-(benzyloxy)phenol (34.0 g, 0.17 mol), concentratedhydrochloric acid (0.20 ml, 37%) and 300 ml of methylene chloride. Addto the resulting suspension drop by drop a solution of 2,3-dihydrofuran(22.8 g , 0.33 mol) and 100 ml of methylene chloride. Stir the mixtureat room temperature under an inert atmosphere for 16 hours at which timeonly trace amounts of 4-(benzyloxy)phenol remain by standard thin layerchromatography analysis (Vogel's Textbook of Practical OrganicChemistry, 5th Edition, p.199). Wash the reaction mixture with aboutthree aliquots of 1N sodium hydroxide, each 300 ml, and back extractsaid aqueous washes with about 200 ml of methylene chloride. Combine theorganic layers, dry over sodium sulfate, and concentrate in-vacuo to anoil. Crystallize 2- (4-benzyloxy)phenoxy!tetrahydrofuran from said oilvia careful trituration with a non-polar solvent such as hexanes;melting point 43°-44° C.

STEP TWO:

Add 55% hydrazine hydrate (1.8 g, 30.0 mmol) to a solution comprising 2-(4-benzyloxy)phenoxy!tetrahydrofuran (2.7 g, 10.0 mmol), 5% Pd/C (0.4 gof 50% wet material) and 50 ml of absolute ethanol. Heat reactionmixture at reflux under an inert atmosphere for about 30 minutes. Coolthe reaction mixture and filter off the catalyst. Concentrate theresulting clear pale yellow filtrate to an oil in-vacuo and co-distillin succession with two aliquots of ethanol (50 ml), two aliquots ofethyl acetate (50 ml) and two aliquots of hexanes (50 ml). Triturate theresulting solid with about 25 ml of hexane and dry in-vacuo at 40° C. toconstant weight. Composition and purity of the cream colored 4-tetrahydrofuran-2-yl)oxy!phenol is confirmed by ¹ H and ¹³ C NMR andelemental analysis; melting point 59°-61° C.

EXAMPLE II

4- (tetrahydro-2H-pyran-2-yl)oxy!phenol is prepared as follows: ##STR5##

STEP ONE:

Slowly add, under an inert atmosphere, a methylene chloride solution of3,4-dihydro-2H-pyran (37.3 g, 0.44 mol) to a solution comprising4-(benzyloxy)phenol (88.8 g, 0.44 mol), concentrated hydrochloric acid(0.25 ml, 37%) and 600 ml of methylene chloride. This reaction mixtureis stirred at room temperature for about 15 minutes, at which time asubstantial amount of 4-(benzyloxy)phenol is present by thin layerchromatography. Add to the reaction mixture two consecutive portions ofa solution comprising 3,4-dihydro-2H-pyran (7.5 g) and 25 ml ofmethylene chloride. Stir the mixture for about 1 hour wherein only traceamounts of starting phenol remain.

Wash the reaction mixture with about three aliquots of 4% aqueous sodiumhydroxide, each 400 ml. Separate the aqueous layer and back extract saidlayer with about 100 ml of methylene chloride. Combine the organiclayers, dry over sodium sulfate, and concentrate in vacuo at about 40°C. to a volume of about 200 ml. Remove excess methylene chloride byco-distilling said concentrate with a sufficient amount of hexane tobring the total volume of the distillate to about 250 ml. Dilute theresulting white suspension with hexane and cool said mixture to aboutambient temperature. Collect the precipitated intermediate, 2-(4-benzyloxy)phenoxy!tetrahydropyran, on a filter and wash in-situ with100 ml aliquots of hexane. Dry said precipitate in vacuo at about 35° C.until a constant weight is obtained; melting point 70°-71° C.

STEP TWO:

Add 55% hydrazine hydrate (34.85 g, 0.6 mol) to a stirred suspensioncomprising 2- (4-benzyloxy)phenoxy!tetrahydropyran (56.4 g, 0.2 mol), 5%Pd/C (4.1 g of 50% wet material) and about 450 ml of absolute ethanol.Slowly heat the reaction mixture and maintain at reflux under an inertatmosphere until thin layer chromatography analysis indicates completeconsumption of 2- (4-benzyloxy)phenoxy!tetrahydropyran. Cool thereaction mixture to about 50° C., clarify said mixture by filtration,and concentrate to a solid in-vacuo at 40° C. Suspend said solid inethanol and slowly dilute said suspension with de-ionized water. Stirfor about 30 minutes and collect the white solid on a filter. Wash saidsolid in-situ with water, then re-suspend the solid in water. Re-collectthe solid, wash in-situ with water and dry in-vacuo at 24° C. toconstant weight.

Further purification of 4- (tetrahydro-2H-pyran-2-yl)oxy!phenol, ifnecessary, is achieved by a second round of recrystallization fromaqueous ethanol. Composition and purity is confirmed by ¹ H and ¹³ C NMRand elemental analysis; melting point 86°-87° C.

EXAMPLE III

4- (1-butoxyethyl)oxy!phenol is prepared as follows: ##STR6##

STEP ONE:

In similar fashion to Examples I and II, slowly add a methylene chloridesolution of butyl vinyl ether (6.2 g, 0.06 mol) to a solution comprising4-(benzyloxy)phenol (12.4 g, 0.06 mol), concentrated hydrochloric acid(0.15 ml, 37%) and 100 ml of methylene chloride. Stir under an inertatmosphere for about 2 hours and analyze reaction mixture for4-(benzyloxy)phenol by thin layer chromatography. If 4-(benzyloxy)phenolis still present, add to said reaction mixture a further portion ofbutyl vinyl ether (1.8 g, 0.02 mol) in 25 ml of methylene chloride andcontinue to stir until the phenol is consumed.

Wash the reaction mixture with about three aliquots of 1N sodiumhydroxide, each 250 ml, and back extract said aqueous washes with about100 ml of methylene chloride. Combine the organic layers, dry oversodium sulfate, and concentrate benzyl protected intermediate in-vacuoto a pale yellow oil. Composition and purity of intermediate isconfirmed by ¹ H and ¹³ C NMR.

STEP TWO:

Add 55% hydrazine hydrate (2.5 g, 0.078 mol) to a stirred suspensioncomprising intermediate from step one (5.0 g, 0.017 mol), 5% Pd/C (3.8g) and about 100 ml of methanol. Heat the reaction mixture and maintainat reflux under an inert atmosphere for about 2 hours whereupon thinlayer chromatography analysis indicates complete consumption of thebenzyl protected intermediate. Cool the reaction mixture to roomtemperature and filter off the catalyst. Concentrate the resulting clearpale yellow filtrate to an oil in-vacuo, wash with hexanes and dry toconstant weight in-vacuo at 50° C. Composition and purity of isolated 4-(1-butoxyethyl)oxy!phenol is confirmed by ¹ H and ¹³ C NMR.

What is claimed is:
 1. The reaction product made by the processcomprising the steps of:a) reacting monoether of hydroquinone with anenol ether in the presence of an acid catalyst to yield an intermediatemonoacetal of hydroquinone that is protected by an ether protectinggroup; and b) reacting said intermediate with a hydrogen transfer sourcein the presence of a metal catalyst such that the ether protecting groupis selectively cleaved to thereby provide a reaction mixture rich inhydroquinone monoacetal.
 2. The product according to claim 1 wherein theether protecting group is selected from the group consisting ofarylmethyl, diarylmethyl, triarylmethyl, trimethylsilyl ethers andmixtures thereof.
 3. The product according to claim 2 wherein the etherprotecting group is an arylmethyl ether.
 4. The product according toclaim 3 wherein the arylmethyl ether is selected from the groupconsisting of benzyl ethers, aliphatic benzyl ethers and mixturesthereof.
 5. The product according to claim 4 wherein the arylmethylether is an aliphatic benzyl ether or benzyl ether.
 6. The productaccording to claim 5 wherein the arylmethyl ether is monobenzyl ether.7. The product according to claim 1 wherein the hydrogen transfer sourceis non-acidic and selected from the group consisting of hydrazine,ammonium formate, trialkylammonium formates, and mixtures thereof, in amolar ratio of hydrogen transfer source to intermediate from about 6:1to about 1:1.
 8. The product according to claim 7 wherein the hydrogentransfer source is hydrazine in a molar ratio of hydrazine tointermediate product of about 4:1 to about 2:1.
 9. The product accordingto claim 1 wherein the formation of the intermediate is carried out in apolar organic solvent.
 10. The product according to claim 9 wherein thepolar organic solvent is selected from the group consisting of methylenechloride, diethylether, tetrahydrofuran, dioxane and mixtures thereof.11. The product according to claim 10 wherein the polar organic solventis methylene chloride.
 12. The product according to claim 1 wherein themetal catalyst is a carbon supported metal selected from the groupconsisting of palladium, platinum, nickel and mixtures thereof, whereinthe weight percentage of metal in the supported catalyst is from about2-20%.
 13. The product according to claim 12 wherein the metal catalystis palladium on carbon.
 14. The product according to claim 1 wherein thereaction of the intermediate and the hydrogen transfer source is carriedout in a polar organic solvent.
 15. The product according to claim 14wherein the polar organic solvent is a hydroxy solvent.
 16. The productaccording to claim 15 wherein the hydroxy solvent is selected from thegroup consisting of methanol, ethanol, isopropanol and mixtures thereof.17. The product according to claim 16 wherein the hydroxy solvent ismethanol or ethanol.